Dysfunction in tyrosine kinase activity disrupts the nor-mal control of cellular phosphorylation signaling pathways,which plays a vital role in genesis and development of various tumors, and makes tyrosine kinases a class of targets of many anti-tumor drugs. Currently most approved tyrosine kinase inhibitors ( TKIs) are based on irreversible binding mechanisms, making them poorly selective, not potent or sustained enough regarding pharmacological effects and prone to triggering resistance. In the past decade, much progress has been made in the development of
a new class of TKIs which irreversibly inhibit their target proteins via the formation of covalent bonds, overcoming the drawbacks of irreversible TKIs. Several irreversible TKIs have entered markets or clinical research phases. This review is to summarize the structural, pharmacological and medicinal chemical properties of investigational and marketed irreversible TKIs as well as their re-cent developments.

Objective To compare the Health Related Quality of Life (HRQOL) of patients with sys temic lupus erythematosus (SLE) with other common chronic diseases (coronary heart disease,diabetes and hypertension).Methods Responses from Short Form-36 (SF-36) questionnaires from outpatients,inpatients with SLE,other common chronic diseases and healthy controls were analyzed in all domains.Results The mean age of patients with SLE was 39+13 years old,while those of patients with coronary heart disease,dia betes and hypertension were 65±16,60±13,59±14 years respectively.All SLE patients were significantly worse in all domains of SF-36 questionnaire,compared with the healthy controls.The responses of inactive patients with SLE,were not significantly worse than those with other chronic diseases in all domains (P＞0.05).On the contrary,the responses of patients with active SLE were significantly worse than those of patients with inactive SLE,as well as patients with other chronic diseases (P＜0.05).Conclusion HRQOL of patients with active SLE is significantly worse when compared to patients with other common chronic diseases.

Objective To establish an efficient HPLC method for the determination of uric acid in plasma of hyperuricemia model mice,and the evaluation of uric acid lowering effect of Lesinurad.Methods The Laballiance Series Ⅲ HPLC system was adopted with Kromasil C18 column (100 mm × 4.6 mm,5 μm).The mobile phase consisted of methanol-0.5％ acetic acid (10:90) for isocratic elution with a flow rate of 0.4 mL/min.The detection wavelength was set at 283 nm.The established HPLC method was used to detect the plasma uric acid level of mice at 0.5,1.0,and 2.0 h time points after which being ip injected with 250 and 500 mg/kg uric acid.Lesinurad of 250 and 500 mg/kg was ig given to mice,0.5 h later,mice were ip injected with 500 mg/kg uric acid to establish hyperuricemia model,and 1 h later,the established HPLC method was used to detect the plasma uric acid level of mice.Results There was a good linear relationship between peak area and the concentration of plasma uric acid in the range of 7.5-150 μg/mL (r =0.997).The specificity,repeatability,precision,stability,and recovery of the established HPLC method was in accordance with the guiding rules of biological sample determination.Compared with the endogenous serum uric acid concentration of control group mice,serum uric acid concentration of 250 mg/kg dose group was significantly increased 0.5 h after ip administration with uric acid (P ＜ 0.01),and serum uric acid concentration of 500 mg/kg dose group was significantly increased 0.5,1.0,and 2.0 h after ip administration with uric acid.Compared with model group,the concentration of uric acid in plasma decreased significantly in low dosage group administered with Lesinurad (P ＜ 0.05),while decreased more significantly in high dosage group (P ＜ 0.01).Conclusion This convenient,rapid,and accurate method can be applied to the determination of uric acid in mouse plasma and the evaluation of relative drugs,which provide an efficient analysis way for establishing hyperuricemia model and screening relative drugs.

Objective To investigate the rational method of treatment of rectal carcinoid and its outcome.Methods The clinical data of 36 cases of rectal carcinoid were retrospectively analysed.Results During a follow-up of 82.6+/-63.4 months,there were no cases with recurrence among the 20 patients with tumor size2cm.Conclusions Tumor diametar can be used to estimate the degree of malignancy of rectal carcinoid.TNM staging is simpler and practical for deciding the method of surgical treatment.

Purpose To study the expression of HIF-1αand Glut-1 in the molecular subtypes of breast carcinoma and their correlation with basal-like breast carcinoma. Methods 803 cases of invasive breast carcinoma from our database were identified. The clinicopath-ologic findings and the biologic markers including estrogen receptor ( ER) , progesterone receptor ( PR) , and human epidermal growth factor receptor-2 (HER-2) status were reviewed. Immunohistochemical MaxVision stains for cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor ( EGFR) were performed. All breast carcinomas were subclassified into Luminal A, Lumincal B, HER-2 over-expression, normal-like, and basal-like subtypes according to Nielsen criteria. Immunohistochemical stain was also used to detect the expression of HIF-1αand Glut-1. Results Positive expression rates of HIF-1αprotein in basal-like, HER-2 over-expression, normal-like, Luminal A and Luminal B substypes were 77. 89% (74/95), 56. 06% (37/66), 55. 76% (92/165), 31. 97% (141/441), 25. 00% (9/36), respectively. The positive expression rates of Glut-1 protein were 80. 00% (76/95), 57. 58% (38/66), 58. 18%(96/165), 34. 01% (150/441), 25. 00% (9/36), respectively. The positive expression rates of HIF-1α and Glut-1 in the basal-like, HER-2 over-expressing and normal-like subtypes were remarkably higher than that in Luminal A and Luminal B subtypes ( P<0. 004 5) and the expression of HIF-1a and Glut-1 was negatively correlated with the expression of ER (P<0. 01). In the ER-negative breast cancers, the positive expression rates of HIF-1a and Glut-1 in basal-like substype were much higher than that in the other sub-types (P<0. 004 5), and the expression of HIF-1α was positively correlated with expression of Glut-1 in basal-like breast carcinoma (P<0. 01). Conclusion The overexpression of HIF-1αand Glut-1 may be closely related to the ER-negative breast cancer and HIF-1α and Glut-1 might play an important role in the development of basal-like breast carcinoma.

Monoclonal antibody ( mAb ) represents a class of therapeutics experienced dramatic development over the past 30 years. Because of the tremendous differences in physicochemical and biological properties between mAbs and small molecules, the mAb therapeutics significantly differ from the chemical drugs in pharmacokinetic characteristics and underlying mechanisms. Full understanding of those characteristics and mechanisms may efficiently guide the screening and development of mAb medi-cines, and would well support their safety evaluation and clinical dosage regimen designing. This review is to summarize pharma-cokinetics and underlying mechanisms of mAbs from the aspects of absorption, distribution and elimination, as well as the ap-proaches for prediction of mAb pharmacokinetics in humans.

Antibody-drug conjugate (ADC) is a new class of therapeutics composed of a monoclonal antibody and small cytotoxin moieties conjugated through a chemical linker. ADC molecules bind to the target antigens expressed on the tumor cell surfaces guided by the monoclonal antibody component. The binding ADC molecules can be internalized and subsequently the toxin moieties can be released within the tumor cells via chemical and/or enzymatic reactions to kill the target cells. The conjugation combines the merits of both components, i.e., the high target specificity of the monoclonal antibody and the highly potent cell killing activity of the cytotoxin moieties. However, such complexities make the pharmacokinetic and metabolic studies of ADCs highly challenging. The major challenges should include characterization of absorption, distribution, metabolism and excretion, investigation of underlying mechanisms, assessment of pharmacokinetic- pharmacodynamic relationship, and analytical method development of ADC drugs. This review will discuss common pharmacokinetic issues and considerations, as well as tools and strategies that can be utilized to characterize the pharmacokinetic and metabolic properties of ADCs.

OBJECTIVE: To compare the mid- and long-term outcomes of patients receiving mitral valve replacement through robotically assisted and conventional median sternotomy approach. METHODS: The data of 47 patients who underwent da Vinci robotic mitral valve replacement in our hospital between January, 2007 and December, 2015 were collected retrospectively (robotic group). From a total of 286 patients undergoing mitral valve replacement through the median thoracotomy approach between March, 2002 and June, 2014, 47 patients were selected as the median sternotomy group for matching with the robotic group at a 1:1 ratio. The perioperative data and follow-up data of the patients were collected, and the quality of life (QOL) of the patients at 30 days and 6 months was evaluated using the Quality of Life Short Form Survey (SF-12). The time of returning to work postoperatively and the patients' satisfaction with the surgical incision were compared between the two groups. RESULTS: All the patients in both groups completed mitral valve replacement successfully, and no death occurred during the operation. In the robotic group, only one patient experienced postoperative complication (pleural effusion); in median sternotomy group, one patient received a secondary thoracotomy for management of bleeding resulting from excessive postoperative drainage, and one patient died of septic shock after the operation. The volume of postoperative drainage, postoperative monitoring time, ventilation time, and postoperative hospital stay were significantly smaller or shorter in the robotic group than in the thoracotomy group ( CONCLUSIONS Robotically assisted mitral valve replacement is safe and reliable. Compared with the median sternotomy approach, the robotic approach is less invasive and promotes faster postoperative recovery of the patients, who have better satisfaction with the quality of life and wound recovery.
COVID-19/drug therapy* ; Humans ; Mitral Valve/surgery* ; Quality of Life ; Retrospective Studies ; Robotic Surgical Procedures ; Sternotomy ; Thoracotomy ; Treatment Outcome